Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system which is characterized by a gradual deterioration of cognitive function. The etiology of AD is unknown, and there is currently no cure or effective treatment for the disease. This Program Project Proposal is directed at developing intracerebral grafting of genetically modified cells as a therapeutic approach for treating age-related cognitive decline. There are two strategies which are proposed in the current Proposal. It is clear that certain neuronal populations degenerate within the AD brain. Thus, one method for delaying the onset of cognitive dysfunction in AD may be to protect vulnerable neurons from dying. Project 1 of this Program will develop genetically modified cells to produce trophic factors which may be effective in supporting the survival of CNS neurons. This Project will initially focus on nerve growth factor, since this factor has been shown to support the survival of cholinergic neurons, but will expand to explore other factors which have been identified as trophic molecules. A second strategy for treating age-related cognitive decline is to replenish neurotransmitters which are depleted in the AD brain. This is currently the most common therapy for AD, although the results using systemic pharmacological treatments have not been robust. Thus, Project 2 will focus on developing cells to produce neurotransmitters which are decreased in the AD brain. Implanting trophic- or neurotransmitter-producing cells directly within appropriate target regions of the brain should enhance the efficacy of the secreted product. Projects 1 and 2 will be conducted in the rodent system, and a third Project will translate these strategies to primates. A research and service Core will provide the cellular and molecular support for all three Projects and will develop new and innovative ways to handle donor cells and obtain transduced cells which produce desired levels of trophic molecules or neurotransmitters.